Postoperative delirium (POD), a clinical phenomenon different from postoperative cognitive dysfunction, is the most common postoperative complication among older patients and is associated with substantially increased rates of morbidity and mortality, as well as an increased cost of care, and risk of developing Alzheimer's disease and related dementias (ADRD). Specifically, people with ADRD are at an increased risk of developing delirium, and dementia-free patients who experience delirium are at higher risk of developing ADRD. However, the pathogenesis of POD is still largely unknown, and this gap in knowledge impedes current efforts in preventing and treating POD. To further study the POD pathogenesis, we have established a rodent model, called the Confusion Assessment Method (CAM) in mice, to assess the delirium-like behavior in mice. Consistent with the notion that Tau phosphorylation and neuroinflammation are part of ADRD neuropathogenesis and are associated with cognitive impairments, our preliminary studies showed that open abdominal surgery under general anesthesia (anesthesia/surgery) induced neuroinflammation and POD-like behavior in aged mice which had elevated levels of brain phosphorylated Tau (pTau). Thus, the proposed research will extend these studies to define a potential multifactorial model of POD pathogenesis by testing the following hypothesis: anesthesia/surgery-induced neuroinflammation is exacerbated by aging- or AD gene mutation-associated accumulation of brain pTau, leading to neuronal dysfunction and POD-like behavior in mice. We will employ biochemical and genetic tools through both in vivo (mice) and in vitro (neuron and microglia) approaches to accomplish three Specific Aims: 1) We will evaluate the effects of abdominal surgery under anesthesia with 1.4% isoflurane, 3% sevoflurane or 9% desflurane for two hours on plasma and brain levels of IL-6 and pTau, microglia activation, neuronal dysfunction, and POD-like behavior in mice. 2) We will perform in vitro studies to determine the trafficking of neuronal pTau and microglia IL-6, and their effects on each other's generation and consequent neuronal dysfunction, using the neurons and microglia harvested from wild-type, IL-6 knockout and Tau knockout mice. 3) We will assess whether knockout of IL-6 or Tau, anti- inflammatory treatments (naproxen and parecoxib) or Tau phosphorylation inhibitor (lithium) can mitigate the anesthesia/surgery-induced neuronal dysfunction and POD-like behavior in mice. We will include adult wild- type (3 months-old) mice versus age matched (3 months-old) AD transgenic and aged wild-type (18 months- old) mice (with higher pTau levels), and employ a label-free nano-biosensing system for biomolecular analysis (nanobeam technology), calcium imaging, in vitro electrophysiology, microdialysis, and CAM in mice. This proposal aims to investigate an understudied topic in innovative systems through testing novel hypotheses. Our efforts could ultimately help to develop prevention and treatment methods towards POD, leading to safer surgical care and better post-operative outcomes for senior and ADRD patients.